1. Case Report and Lit Review: Reduction of Proteinuria in Diabetic Nephropathy with Spironolactone Harry W. Floyd, M.D. Family Medicine Kingstree, South Carolina Case Presentation History: Mr. O.G. is a 49 year old man who initially presented to my practice with hypertension and diabetes mellitus. He had a brother who was on dialysis prior to his death from end-stage renal disease at 30 years of age. Mr. O.G. was desperately afraid he was headed in the same direction. In 2001, his BP was 144/92 mmHg with serum creatine 1.1 mg/dL, eGFR 86, and urine protein 4+. He was placed on Altace 10 mg twice daily with a reduction of BP to 136/84. However, he continued to spill 4+ protein in his urine. Diovan 320 daily was added with a modest decline of BP to 130/80, but he still had 4+ urine protein. A 24-hour urine had 8.4 grams protein and repeat serum creatinine was 1.2 mg/dL (eGFR 78). Tekturna was then added with further lowering of blood pressure to 124/76, but urine protein remained 4+. A nephrology consultation was obtained but did not significantly alter his therapy or proteinuria. I began thinking in terms of the concept of hyperfiltration in the diabetic kidney and the kidney as a semi- permeable membrane. I postulated that hyperfiltration could only be accomplished by increase in both volume and pressure; therefore, if the volume of the flow could be decreased, then glomerular pressure would also fall. Management: Spironolactone Added Given these assumptions, Mr O.G. was started on spironolactone 25 mg, ramipril was stopped and serum K + and urine protein were followed closely. The patient was fully informed about the risks and benefits of the drug. The urine protein fell to 3+, and the spironolactone dose was increased from 25 mg to 50 mg. Urine protein declined further to 2+ with serum K+ 4.7–4.8 mEq/L. Encouraged by the progress, spironolactone was increased to 75 mg /d. Complication of Spironolactone Therapy Mr. O.G. decided to eat peaches on a recurring basis for his bed time snack. On return one month later, his urine dipstick showed only a trace of protein, but his K + was 6.0 mEq/L (normal 3.6–5.5). I called the patient and immediately stopped spironolactone. His K + normalized at 4.5 mEq/L but urine protein returned to 4+. Next Steps Cautiously, the spironolactone was restarted and gradually increased it to 50 mg daily. He has been stable with a serum creatinine of 1.3, eGFR 71, and K + of 4.8 for 4 years. BP and diabetes remain well controlled at 110/70 mmHg and HbA1C 6.2%, respectively. While 24-hour protein is elevated at 492 mg, that represents a dramatic decline of nearly 95% from the baseline of 8.4 grams per 24 hours. Literature Review: Spironolactone and Proteinuria It has been fascinating to see confirmation of this concept 1 that spironolactone is a useful therapeutic tool for reducing proteinuria. 2–6 In fact, published reports and studies document that addition of spironolactone to an ACE inhibitor and/or angiotensin-receptor blocker produces large and sustained decreases of urine protein excretion. Some studies documented slowing in the loss of renal function after the expected initial decline. Of note, much of this work has been done in patients with diabetic nephropathy. As observed in Mr. O.G., clinically significant hyperkalemia is a risk of combining an aldosterone antagonist with a RAS blocker in patients with diabetic nephropathy and requires careful monitoring after adding an aldosterone antagonist and after changing dose. As shown in Figure 1 (ref 3), proteinuria decreased progressively during the initial 12 months of therapy and was greater among patients with baseline GFR 60 ml/min from the 6 th through 12 th month. Conclusion Diabetes is the leading cause of end-stage renal disease. Aldosterone antagonists provide an additional therapeutic option for reducing proteinuria / albuminuria with evidence suggesting renal survival is prolonged. 2-5 Hyperkalemia is a risk. 6 This risk can be managed by identifying those at greatest risk, e.g., eGFR 4.5 and either not starting them on spironolactone or beginning a low dose, e.g., 12.5 mg daily, educating them to avoid foods and beverages with high potassium content, and following up with a chemistry profile in one week. Good clinical judgment is paramount in assessing risk and benefit. Given the growing epidemic of diabeteic end-stage renal disease, aldosterone antagonists are an often overlooked option for reducing proteinuria and preserving renal function. Effects of Adding Spironolactone 25 mg/d to ACEI &/or ARB vs. ACEI &/or ARB on Proteinuria and eGFR in 165 CKD Patients. 3 Quantifying the Risk and Predictors of Hyperkalemia in Patients Treated with Spironolactone The risk of hyperkalemia in 46 patients with Stage 2–3 CKD (eGFR 30– 89, mean eGFR 56) was studied. 6 Their mean age was 65 years; 86% were diabetic. On average, serum K + rose 0.4 mEq/L. As expected, the risk of hyperkalemia was greater when baseline eGFR was 4.5. The risk of hyperkalemia was also greater when systolic BP fell >15 mmHg and eGFR fell >30%. In ASCOT, 1411 of 19,257 hypertensive patients were not controlled on 3 BP medications, i.e., treatment resistant. Spironolactone was added at a mean dose of 25 mg /d in this group, mean age 63.5 years, 40% diabetic, mean eGFR ~64. BP fell 22/10 6% developed a serum K+ >5.5 and 2% >6.0 mEq/L. 7 References 1.Kidney International. 1997;63:S115–S119. 2. J Hypertens. 2006;24:2285–2292. 3.Kidney International. 2006;70:2116–2123. 4. Clin J Am Soc Neph. 2006;1:256–62. 5.Clin Exper Nephrol. 2009;13:663–666. 6. Am J Nephrol. 2009;30:418–424. 7. Hypertension. 2007;49:839–845.